How are the characteristic electrical properties of neurons regulated to maintain appropriate circuit performance? This proposal combines experimental and theoretical approaches to study the mechanisms underlying homeostatic regulation of neuronal excitability in numerous cell types. Three specific aims are proposed: i) To study the role of activity patterns and neuromodulation in the long-term regulation of electrical activity in identified neurons of the crustacean stomatogastric ganglion, 2) Identification of candidate kinase and phosphatase molecules likely to be part of the homeostatic set-point and read-out mechanisms in the identified neurons in the crustacean stomatogastric nervous system, and 3) Construction and study of homeostatic models that can allow neurons to regulate and tune their firing rate set-points and rhythmic behaviors. These models are based on the premise that somatic Ca2+ concentrations can be read-out by appropriate kinases and phosphatases which then control the numbers and types of ion channels in the membrane, and therefore the neurons' excitability. Models will be developed that account for the firing rate set- points of the tonically firing neurons studied in Projects 1-3, as well as those studied experimentally in this project. Comparison of these models will illuminate the extent to which the regulation of neuronal excitability in different neuron types depends on conserved mechanisms. RELEVANCE (See instructions): It is likely that dysregulation of the homeostatic processes that regulate neuronal excitability plays a role in numerous neurological disorders, including spinal cord spasticity, neuropathic pain, and epilepsy. The proposed work addresses the core problem of the mechanisms that allow neurons to appropriately determine their own electrical properties, and therefore maintain healthy circuit performance. PROJECT/PERFORMANCE SrrE(